Prior research indicates that evidence of brain aging (amyloid senile plaque [SP] and neurofibrillary tangle [NFT] accumulation, neuroreceptor decline) occurs decades before individuals reach the age at risk for dementia. Moreover, current methods for detecting pre-symptomatic dementia and differentiating types of dementia are imprecise. To address these issues, this project will clarify patterns of SP and NFT brain accumulation in cognitively intact individuals (ages 30 to 80 years), individuals with MCI, and patients with mild AD and frontotemporal dementia (FTD), using 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-2- naphthyl}ethylidene)malononitrile ([18FJFDDNP-PET) scan imaging. Cerebral patterns of SP and NFT will be determined along with informative clinical, neuropsychological, and genetic risk measures, as well as measures of regional cerebral glucose metabolism, using flurodeoxyglucose ([18F]FDG)-PET. To further clarify patterns of neurodegeneration in subjects with AD, MCI, and older controls, serotonin receptor density will be determined, using [18F]MPPF-PET. At baseline, all subjects will receive [18F]FDDNP-PET, [18F]FDG-PET, and structural MRI (in order to co-register PET data for imaging analysis) scanning, as well as genetic risk testing (e.g., APOE, H1/H1 haplotype), and clinical, behavioral, and neuropsychological assessments. Older subjects also will receive [18F]MPPF scans to measure levels of 5-HT1A receptors. Cognitively intact middle-age and older subjects, individuals with MCI, and patients with AD will be followed longitudinally, and after two years, imaging, clinical, and neuropsychological assessments will be repeated. The aims of this project are to: (1) Determine how SP and NFT brain accumulation patterns differ according to age, dementia diagnosis, and genetic risk, and how these measures correlate with patterns of neuronal deterioration; (2) Measure 5-HT1A receptor levels throughout the brain, particularly in the medial temporal lobe, and compare these signals to [18F]FDDNP measures of plaque and tangle burden, as well as regional glucose metabolic rates; and (3) Determine whether [18F]FDDNP-PET patterns and/or [18F]MPPF-PET patterns predict future cognitive and metabolic decline, and SP and NFT accumulation in the brain. This project will lead to more effective diagnosis and differential diagnosis of dementia and age-related memory loss and will provide the groundwork for reliable methods of testing interventions designed to delay the onset of dementia and treat it once it develops.